Crohn's Disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that leads to severe impairments of quality of life and substantial health care costs. The disease results from altered immune responses to intestinal bacteria and other microbes, and frequently is driven by susceptibility genes. The Immunity Related GTPase (IRG) M gene is a recently identified CD susceptibility gene. IRGM encodes a protein that regulates autophagy and mitophagy; however, how IRGM impacts CD pathogenesis is unknown. The goal of the proposed work is to establish a mouse system to model the function of IRGM function with respect to autophagy and intestinal biology. We have found that mouse Irgm1 that shares with human IRGM the ability to modulate autophagy and mitophagy. Additionally, Irgm1-deficient mice exhibit enhanced intestinal inflammation when challenged with experimental models of colitis. These and other preliminary data establish a working hypothesis: Lack of autophagic function due to Irgm1 deficiency leads to impaired functioning in different populations of immune cells that collectively contribute to enhanced intestinal inflammation. The primary goals of this proposal will be: (1) to discern the specific immune processes regulated by Irgm1 in the intestine that are key in modulating intestinal inflammation, and (2) to determine the underlying Irgm1-regulated molecular pathways that instruct those immune functions, particularly the role of autophagy and mitophagy. The following specific aims will be addressed: Aim 1A. Determine whether Irgm1 promotes immune responses in the intestinal epithelium important for controlling intestinal bacteria. Aim1B. Determine whether Irgm1 promotes immune processes in hematopoietic cells - either homeostatic or inflammatory - in response to intestinal bacteria. Aim 1C. Determine which Irgm1-mediated immune responses and cell types are key in suppressing excessive intestinal inflammation. Aim 2A. Determine whether Irgm1 promotes intestinal immune function by stimulating autophagy. Aim 2B. Determine whether Irgm1 promotes intestinal immune function by stimulating a type of autophagy called mitophagy. These studies will fill a major knowledge gap by modeling how an important CD susceptibility gene, IRGM, affects immune homeostasis in the intestine, potentially establishing future therapeutic targets. The studies will also increase understanding of how autophagic processes modulate intestinal immunity, a question that is broadly relevant, as a number of CD susceptibility genes and mouse models are now known to perturb autophagic responses.